Rat and mouse tissue-mediated mutagenicity of ring-substituted 3,3-dimethyl-1-phenyltriazenes in Salmonella typhimurium

Malaveille, Christian; Kolar, G.F.; Bartsch, Helmut

doi:10.1016/0027-5107(76)90015-4

Cited by 39 publications

(8 citation statements)

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“…The origin of arenediazonium ions by hydrolysis of triazenes (pathways A and B1) has been repeatedly reported (Kolar & Preussmann, 1971, Preussmann et al, 1974, Kolar et al, 1974, Malaveille et al, 1976, Kolar, 1984, Gescher & Threadgill, 1987. Kolar & Preussmann, (1971) determined the half-life of a series of 1-aryl-3.3-dimethyltriazenes at pH 7.0 and 37 ° and found values of 210 min for DMPT, 35 min for DMpMPT and 232 000 min for DMpNPT which roughly corresponds to our data.…”

Section: Sister Chromatid Exchange Rates and Cell Cycle Delay Inducedsupporting

confidence: 66%

“…To our knowledge, three of the compounds (DMPT, DMpMPT, and DEPT) have been checked so far for genotoxic activity by other groups. DMPT was shown to be mutagenic in Salmonella typhimurium G46 only in the presence of phenobarbitalinduced rat liver $9 mix; it was non-mutagenic in combination with $9 mix from non-induced rats or in the direct assay (Malaveille et al, 1976, Bartsch et al, 1980. DMpMPT was tested in S. typhimurium G46 together with rat liver $9 mix and was found non-mutagenic but highly toxic (Malaveille et al, 1976).…”

Section: Introductionmentioning

confidence: 99%

“…DMPT was shown to be mutagenic in Salmonella typhimurium G46 only in the presence of phenobarbitalinduced rat liver $9 mix; it was non-mutagenic in combination with $9 mix from non-induced rats or in the direct assay (Malaveille et al, 1976, Bartsch et al, 1980. DMpMPT was tested in S. typhimurium G46 together with rat liver $9 mix and was found non-mutagenic but highly toxic (Malaveille et al, 1976). In Neurospora crassa and Saccharomyces cerevisiae, DMPT induced forward mutations (Ong & de Serres, 1973) and mitotic gene conversion (Fahrig, 1971;Vogel et al, 1973), but it could not be clarified whether or not the genetic activity was due to either the direct action of the substance, to its hydrolysis products or to metabolic activation.…”

Section: Introductionmentioning

confidence: 99%

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Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells

et al. 1991

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A series of seven 1-aryl-3.3-dialkyltriazenes, including 1-phenyl-3.3-dimethyltriazene (DMPT), 1-phenyl-3.3-di-(trideuteromethyl)-triazene (DMPT-ds), 1-p-methylphenyl-3.3-dimethyltriazene (DMpMPT), 1-p-nitrophenyl-3.3-dimethyltriazene (DMpNPT), 1-phenyl-3.3-diethyltriazene (DEPT), 1-phenyl-3.3-di-n-propyltriazene (DnPrPT) and 1-phenyl-3.3-diisopropyltriazene (DiPrPT) and 1.3-diphenyl-3-methyltriazene (DPMT), was synthesized and characterized by UV/VIS, IR and 1H-NMR spectroscopy. Chemical half-life was determined in phosphate buffer at 37 degrees using UV/VIS spectroscopy. With the exception of DMpNPT, which was stable, the triazenes underwent pH-dependent hydrolytic decomposition (acid catalysis). By means of UV/VIS spectra, TLC and HPLC, phenol, aniline and secondary azocoupling products were identified after complete hydrolytic cleavage of the parent compounds. Pathways of spontaneous hydrolysis are proposed and discussed. Genotoxic activity of the triazenes was assayed by measurement of sister chromatid exchanges (SCE) in V79-E cells without and with rat liver S9 mix as an exogenous metabolizing system. In the direct SCE assay (without S9 mix), all triazenes except DMpNPT exerted a toxic action (cell cycle delay) in a narrow concentration range between no effect and overt cytotoxicity. This non-specific toxicity depended on the pH of the incubation system and was inversely proportional to chemical half-life. The toxicity of these agents is most likely due to the arenediazonium cation which is a relatively stable intermediate. In a sublethal concentration range most triazeness induced significant increases of SCE rates. These are interpreted as an indirect consequence of cytotoxicity. Upon metabolic activation, the compounds were genotoxic in a dose-dependent fashion. Their SCE-inducing capacity depended on the nature of the alkylating species generated, i.e., the alkyldiazonium cation, and on chemical stability. Surprisingly, no deuterium isotope effect was observed in DMPT-d6. The order of genotoxic activity among the aryldialkyltriazenes was DMpNPT much greater than DMPT = DMPT-ds greater than DMpMPT much greater than DEPT greater than DnPrPT greater than or equal to DiPrPT. DPMT was a marginal SCE inducer but very toxic upon metabolic activation. As monooxygenation of DPMT, like spontaneous hydrolysis, should generate a phenyldiazonium cation, the results suggest that arylation of DNA causes a very low SCE induction, if any.

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Section: Sister Chromatid Exchange Rates and Cell Cycle Delay Inducedsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells

et al. 1991

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“…3,3-Dimethyl-1-phenyltriazene (DMPT) is a nethylating agent that is mutagenic ( 11,28,41,46), teratogenic (18, 34), and carcinogenic (16,40). As a teratogen, DMPT has a remarkable lack of phase specificity in that the targets are not significantly influenced by administration on different days of gestation (Frank, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

et al. 1992

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Exposure of rat embryos to 3,3-dimethyl-1-phenyltriazene (DMPT) results in numerous malformations, but the urogenital system is not affected. In contrast, exposure of rat fetuses to DMPT has been reported to result in renal neoplasms, which were not further classified. To better understand this discrepancy in organotropism of the teratogenic and transplacental carcinogenic processes, the present study was undertaken to characterize the neoplasms induced in rat fetuses exposed to DMPT in utero. Renal neoplasms and persistent mesenchyme were observed in 19.2 and 11.5%, respectively, of the offspring of rats treated with 1 mg DMPT/ kg body weight intraperitoneally on gestation days 16, 18, and 20. The majority of these renal lesions were observed in females. The renal neoplasms were mixtures of various types of mesenchymal tissue derivatives including smooth muscle and fibrous connective tissue. These neoplasms would be classified as renal mesenchymal tumors in rats. Brain neoplasms (numerous types), compound odontomas, and micrognathism were observed predominantly in male offspring from the same group. This treatment also resulted in decreased body weights, increased incidence of sudden loss of body weight, tremors and ataxia, and hypoplastic testes. Exposure to single intraperitoneal doses of DMPT on gestation day 20 did not produce a classic dose-response pattern: Minimal effects were observed with 10 mg DMPT/kg (occasional renal mesenchymal tumors and brain neoplasms), marked effects were observed with 30 mg DMPT/kg (lower incidence rate of most of the alterations observed with 1 mg/kg on gestation days 16, 18, and 20), and no effects were observed with 60 mg DMPT/kg. DMPT administered intraperitoneally at 1 mg/kg body weight on gestation days 16, 18, and 20 is an animal model of transplacental chemically induced renal neoplasms, which provide lesions with similarities to both intralobar nephrogenic rests and congenital mesoblastic nephroma of humans. Why the kidney is a carcinogenic target and not a teratogenic target remains unknown.

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“…Aryldimethyltriazenes are a class of compounds possessing antitumor (1)(2)(3)(4), carcinogenic (5)(6)(7), and mutagenic (8)(9)(10) activities. Evidence exists that metabolites of these triazenes are responsible for their in vivo effects.…”

mentioning

confidence: 99%

Influence of Serum Albumins on Decomposition Rates of Para- Substituted 1-phenyl-3-methyltriazenes and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide in Near Physiological Conditions

Delben

Paoletti

Manzini

et al. 1981

Journal of Pharmaceutical Sciences

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Rat and mouse tissue-mediated mutagenicity of ring-substituted 3,3-dimethyl-1-phenyltriazenes in Salmonella typhimurium

Cited by 39 publications

References 20 publications

Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells

Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

Influence of Serum Albumins on Decomposition Rates of Para- Substituted 1-phenyl-3-methyltriazenes and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide in Near Physiological Conditions

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